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Definitions

• the present invention relates to a novel indole derivative having a carbamoyl group, a ureido group and a substituted oxy group or a salt thereof useful as a medicine.
• the derivative or a salt thereof has IKK ⁇ inhibitory activity and is useful as a preventive and / or therapeutic agent for diseases associated with IKK ⁇ .
• Nucleofactor ⁇ B (hereinafter referred to as “NF- ⁇ B”), which is involved in signal transduction from the outside of cells into the nucleus, is a transcription factor involved in the expression of many genes induced in immune / inflammatory reactions.
• This transcription factor, NF- ⁇ B normally forms a complex with a regulatory protein called I ⁇ B and is localized in the cytoplasm in an inactive form.
• IKK ⁇ an enzyme responsible for I ⁇ B to phosphorylated by an enzyme called IKK ⁇ , degradation of I ⁇ B proceeds.
• NF- ⁇ B released with the degradation of I ⁇ B becomes an active form, translocates from the cytoplasm into the nucleus and activates transcription of the target gene, tumor necrosis factor (hereinafter referred to as “TNF”), interleukin-1 Production of cytokines such as interleukin-6 (hereinafter referred to as “IL-6”) and cell proliferation are enhanced.
• TNF tumor necrosis factor
• IKK ⁇ can be controlled, the activation of NF- ⁇ B can be inhibited, and the production of cytokines such as TNF, IL-1, and IL-6 and cell proliferation can be suppressed, and these factors may be involved. Can be prevented and / or treated.
• Non-patent literature 1 Various diseases such as rheumatoid arthritis, asthma, diabetes and cancer are known as non-patent literature 1 and patent literature 1 as diseases associated with IKK ⁇ .
• Examples of the compound having IKK ⁇ inhibitory activity include condensed furan derivatives described in Patent Document 1, aromatic heterocyclic 5-membered carboxamide derivatives described in Patent Document 2, and substituted thiophenecarboxamides described in Patent Document 3. Derivatives and the like are known.
• Non-Patent Document 2 a compound having a urea structure at the 2-position of the indole ring is disclosed in Non-Patent Document 2, and a compound having an amide structure at the 3-position of the indole ring is disclosed in Patent Document 4.
• Patent Document 4 a compound having a ureido group at the 2-position of the indole ring, a carbamoyl group at the 3-position, and a substituted oxy group in the benzene ring structure portion on the indole ring. Not done.
• the inventors of the present invention have succeeded in creating a large number of new compounds by conducting synthetic research on a novel indole derivative having a new chemical structure, a carbamoyl group, a ureido group and a substituted oxy group or a salt thereof.
• the present inventors have found that the derivative or salt thereof has IKK ⁇ inhibitory activity and is useful as a pharmaceutical, and completed the present invention. .
• the present invention relates to a compound represented by the following general formula (1) or a salt thereof (hereinafter referred to as “the present compound”) and a pharmaceutical composition containing at least one of the present compounds.
• a preferred invention in the pharmaceutical use relates to an IKK ⁇ inhibitor, and the target diseases include diseases that are associated with IKK ⁇ , such as inflammatory diseases, autoimmune diseases, allergic diseases, infectious diseases, Degenerative diseases, vascular diseases, neuro / sensory organ diseases, endocrine / metabolic diseases, neoplastic diseases, congenital diseases, traumatic diseases, rejection after organ transplantation, etc.
• keratitis Conjunctivitis, uveitis, osteoarthritis, chronic obstructive pulmonary disease, bronchitis, pneumonia, hepatitis, pancreatitis, nephritis, sepsis, systemic inflammatory response syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, Ulcerative colitis, systemic lupus erythematosus, Sjogren's syndrome, polymyositis, dermatomyositis, asthma, allergic rhinitis, hives, atopic dermatitis, age-related macular degeneration, retinopathy of prematurity, Polypoidal choroidal vasculopathy, retinal vein occlusion, diabetes and its complications (diabetic retinopathy, diabetic macular edema, diabetic neuropathy, diabetic nephropathy), leukemia, multiple myelom
• a particularly preferred pharmaceutical use invention is an invention relating to a prophylactic and / or therapeutic agent for the target disease comprising at least one compound of the present invention as an active ingredient.
• R 1 represents a hydrogen atom, a lower alkyl group which may have a substituent, a hydroxy group or a lower alkoxy group which may have a substituent
• R 2 may have a hydrogen atom, a lower alkyl group that may have a substituent, a lower cycloalkyl group that may have a substituent, an aryl group that may have a substituent, or a substituent.
• R 3 may have a halogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group that may have a substituent, a lower alkynyl group that may have a substituent, or a substituent.
• the present invention provides a novel indole derivative having a carbamoyl group, a ureido group and a substituted oxy group or a salt thereof.
• the compound of the present invention has excellent IKK ⁇ inhibitory activity and is useful as an IKK ⁇ inhibitor.
• the compounds of the present invention are particularly diseases in which IKK ⁇ is involved, such as inflammatory diseases, autoimmune diseases, allergic diseases, infectious diseases, degenerative diseases, vascular diseases, neuro / sensory organ diseases, endocrine / metabolic diseases
• inflammatory diseases such as inflammatory diseases, autoimmune diseases, allergic diseases, infectious diseases, degenerative diseases, vascular diseases, neuro / sensory organ diseases, endocrine / metabolic diseases
• Halogen atom refers to a fluorine, chlorine, bromine or iodine atom.
• lower alkyl group refers to a linear or branched alkyl group having 1 to 8, preferably 1 to 6 carbon atoms.
• Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl group and the like. .
• lower alkenyl group refers to a straight or branched alkenyl group having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms. Specific examples include vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, isopropenyl, 2-methyl-1-propenyl, 2-methyl-2-butenyl group and the like.
• lower alkynyl group refers to a straight or branched alkynyl group having 2 to 8, preferably 2 to 6 carbon atoms. Specific examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, isobutynyl, isopentynyl group and the like.
• the “lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl groups.
• Aryl group means a residue obtained by removing one hydrogen atom from a monocyclic aromatic hydrocarbon group having 6 to 14 carbon atoms or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon Indicates. Specific examples include phenyl, naphthyl, anthryl, phenanthryl group and the like.
• Heterocycle means a saturated or unsaturated monocyclic heterocycle or bicyclic or tricyclic ring having one or more heteroatoms selected from nitrogen, oxygen, sulfur and boron atoms in the ring.
• saturated monocyclic heterocycle examples include aziridine, azetidine, pyrrolidine, pyrazolidine, imidazolidine, triazolidine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, homopiperidine, homopiperazine and the like having a nitrogen atom in the ring.
• Tetrahydrofuran, tetrahydropyran, [1,4] dioxane, [1,2] dioxirane, etc. having an oxygen atom in the ring
• tetrahydrothiophene tetrahydrothiopyran, dithiolane, etc.
• these saturated monocyclic heterocycles are condensed with benzene rings and the like to form dihydroindole, dihydroindazole, dihydrobenzimidazole, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydrocinnoline, tetrahydrophthalazine, tetrahydroquinazoline, tetrahydroquinoxaline, dihydrobenzofuran.
• the unsaturated monocyclic heterocycle include dihydropyrrole, pyrrole, dihydropyrazole, pyrazole, dihydroimidazole, imidazole, dihydrotriazole, triazole, tetrahydropyridine, dihydropyridine, pyridine, tetrahydropyridazine, dihydro having a nitrogen atom in the ring.
• dihydrothiophene having a sulfur atom in the ring dihydrothiophene having a sulfur atom in the ring
• Thiophene, dihydrothiopyran, thiopyran, etc. are dihydrooxazole, oxazole, dihydroisoxazole, Kisazoru, dihydro-oxazine, oxazine and the like
• dihydrothiazole having a nitrogen atom and a sulfur atom in the ring thiazole, dihydro-isothiazole, isothiazole, dihydrothiazine, thiazine and the like.
• heterocycles when the heterocycle has two hydrogen atoms on the same carbon atom, these hydrogen atoms are substituted with oxo groups to give 2-pyrrolidone, 4-piperidone, 4-thiazolidone, pyran- Heterocyclic ketones such as 4- (4H) -one and pyrazin-2- (3H) -one may be formed, and such heterocyclic ketones are also included in the scope of the heterocyclic ring of the present invention.
• Heterocyclic group refers to a residue obtained by removing one hydrogen atom from a heterocyclic ring.
• the definition of the heterocyclic ring is applied mutatis mutandis.
• the “lower alkoxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkyl group. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, iso Examples thereof include a pentyloxy group.
• lower alkenyloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkenyl group.
• Specific examples include vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, isopropenyloxy, 2-methyl-1-propenyloxy, 2-methyl-2-butenyloxy and the like.
• lower alkynyloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkynyl group.
• Specific examples include ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, isobutynyloxy, isopentynyloxy groups and the like.
• lower cycloalkyloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower cycloalkyl group.
• Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy groups and the like.
• aryloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aryl group. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy groups and the like.
• heterocyclic oxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a heterocyclic group.
• heterocyclic ring and heterocyclic group described above apply mutatis mutandis.
• Optionally substituted lower alkyl group “optionally substituted lower alkenyl group”, “optionally substituted lower alkynyl group”, “optionally substituted” “Lower alkoxy group which may have a substituent” and / or “lower alkynyloxy group which may have a substituent” include a halogen atom, a lower cycloalkyl group and an aryl group.
• a heterocyclic group a nitro group, a cyano group, —OR P , —COR q , —COOR r , —CONR s R t , —NR u R v and —NHCOR W (preferably a lower cycloalkyl group, An aryl group and a heterocyclic group) which may have one or more substituents selected from “lower alkyl group”, “lower alkenyl group”, “lower alkynyl group”, “lower alkoxy group”, “lower Alkenyloxy "and / or It shows the "lower alkynyloxy group”.
• Optionally substituted lower cycloalkyl group “optionally substituted aryl group”, “optionally substituted heterocyclic group”, “optionally substituted”
• the “lower cycloalkyloxy group”, “aryloxy group optionally having substituent (s)” and / or “heterocyclic oxy group optionally having substituent (s)” are halogen atoms, lower alkyl groups, lower alkenyls Group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, nitro group, cyano group, —OR P , —COR q , —COOR r , —CONR s R t , —NR u R v and —NHCOR (preferably, a halogen atom, a lower alkyl group, a nitro group, -OR P, -NR u R v group consisting of and -NHCOR W) the group consisting of W have one
• R p , R q , R r , R s , R t , R u , R v and R W are the same or different and are a lower alkyl group substituted with a hydrogen atom, a lower alkyl group or a lower alkoxy group. And a group selected from the group consisting of a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, an aryl group and a heterocyclic group.
• the “plural groups” as used in the present invention may be the same or different, and the number is preferably 2 or 3, particularly preferably 2. Further, a hydrogen atom, a halogen atom and a ring are also included in the concept of “group”.
• a plurality of R 3 may be the same or different.
• the “IKK ⁇ inhibitor” referred to in the present invention refers to an agent that exhibits a pharmaceutical action by inhibiting IKK ⁇ .
• diseases associated with IKK ⁇ include inflammatory diseases, autoimmune diseases, allergic diseases, infectious diseases, degenerative diseases, vascular diseases, neuro / sensory organ diseases, endocrine / metabolic diseases, neoplastic diseases And prophylactic and / or therapeutic agents for congenital diseases, traumatic diseases, rejection after organ transplantation, and the like.
• keratitis conjunctivitis, uveitis, osteoarthritis, chronic obstructive pulmonary disease, bronchitis, pneumonia, hepatitis, pancreatitis, nephritis, sepsis, systemic inflammatory response syndrome, rheumatoid arthritis, psoriasis, Multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, Sjogren's syndrome, polymyositis, dermatomyositis, asthma, allergic rhinitis, hives, atopic dermatitis, age-related macular degeneration, retinopathy of prematurity , Polypoidal choroidal vasculopathy, retinal vein occlusion, diabetes and its complications (diabetic retinopathy, diabetic macular edema, diabetic neuropathy, diabetic nephropathy), leukemia, multiple myeloma
• IKK ⁇ is also deeply related to transcription factors NF- ⁇ B and cytokine production (TNF, IL-1, IL-6, etc.), and it is considered that IKK ⁇ of the present invention is also involved in diseases associated with these factors. Enter the range of diseases.
• the “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or the like.
• Salt of organic acid quaternary ammonium salt with methyl bromide, methyl iodide, bromine ion, chloride ion, Salts with halogen ions such as urine ions, salts with alkali metals such as lithium, sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, metal salts with iron and zinc, salts with ammonia , Triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1-methylamino-2-D-sorbitol, 2-amino-2-hydroxymethyl-1,3-propanediol, procaine And salts with organic amines such as N, N-bis (phenylmethyl) -1,2-ethanediamine.
• the crystal polymorph and / or crystal polymorph group (crystal polymorph system) is also included in the present invention.
• the crystal polymorph group refers to crystal forms depending on conditions and / or states (including the formulated state in this state) such as production, crystallization, and storage of the crystals. Means the individual crystal form and / or the whole process at each stage when changes.
• R 1 represents a hydrogen atom, a lower alkyl group which may have a substituent, a hydroxy group or a lower alkoxy group which may have a substituent; and / or (a2) R 2 represents a hydrogen atom, A lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent or a heterocyclic group which may have a substituent; And / or (a3) R 3 has a halogen atom, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent.
• R 1 represents a hydrogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group; and / or (b2) R 2 represents a hydrogen atom, a lower alkyl group or a lower cycloalkyl group which may have a substituent.
• R 3 is a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, A lower cycloalkyl group, an aryl group, a heterocyclic group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group; and / or (b4) m Represents 0, 1 or 2, and when m is 2, R 3 may be the same or different.
• a compound composed of one or more combinations selected from the above (b1), (b2), (b3) and (b4) or a salt thereof can be mentioned. Further, the selected condition can be combined with the condition (a).
• R 1 represents a hydrogen atom
• R 2 has a hydrogen atom, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent.
• R 3 represents a halogen atom, a lower alkenyl group or a heterocyclic group; and / or (c4) m represents 0, 1 or 2, and m represents In the case of 2, R 3 may be the same or different.
• a compound composed of one or more combinations selected from the above (c1), (c2), (c3) and (c4) or a salt thereof can be mentioned. Further, the selected condition can be combined with the condition (a) and / or (b).
• a preferred bonding position of —O—R 2 in the general formula (1) includes a compound bonded to the 6-position of the indole ring of the general formula (1) or a salt thereof.
• the selected conditions can be combined with the conditions (a), (b) and / or (c).
• the compound of the present invention can be produced by the following method.
• each specific manufacturing method is demonstrated in detail by the item of the below-mentioned Example [manufacturing example].
• Hal used in the following synthesis route represents a halogen atom.
• (R) i means an arbitrary substituent represented by R 3 , and i represents 0, 1 or 2.
• the manufacturing method of this invention compound can be divided roughly into the method shown below, and the method can be suitably selected according to the kind of substituent.
• This invention compound (I) can be manufactured according to the synthetic pathway 1. That is, compound (II) and trichloroacetyl isocyanate are -80 ° C. to room temperature in an organic solvent such as tetrahydrofuran (hereinafter referred to as “THF”), N, N-dimethylformamide (hereinafter referred to as “DMF”) or the like.
• THF tetrahydrofuran
• DMF N, N-dimethylformamide
• the compound of the present invention (I) can be obtained by reacting for 1 to 3 hours and then adding an ammonia-methanol solution and reacting at 0 ° C. to room temperature for 1 to 24 hours.
• Compound (II)-(a) and compound (II)-(b) can be produced according to synthetic route 2. That is, compound (V) is prepared by reacting compound (III) with cyanoacetamide (IV) in an organic solvent such as THF or DMF in the presence of a base such as sodium hydride at 0 to 80 ° C. for 1 to 24 hours. Can be obtained. Compound (II)-(a) and compound (II)-(a) and compound (V) obtained by adding metal powder such as iron and zinc and acetic acid in an organic solvent such as toluene and acetic acid at room temperature to 100 ° C. for 30 minutes to 3 hours. Compound (II)-(b) can be obtained.
• the compound (V) is treated in an organic solvent such as methanol or DMF in the presence of palladium carbon in a hydrogen atmosphere at room temperature to 60 ° C. for 1 to 24 hours, or the compound (V) is treated with ammonia in aqueous ammonia.
• Compound (VI) can be obtained by adding sodium thionate and treating at 0 ° C. to room temperature for 30 minutes to 24 hours.
• Compound (II)-(a) can be obtained by reacting the resulting compound (VI) in an organic solvent such as 1,4-dioxane or DMF at room temperature to 150 ° C. for 1 to 24 hours.
• Compound (II)-(a) can also be produced according to Synthesis Route 3 according to the method described in Journal of Heterocyclic Chemistry, 44, 419-424 (2007). That, chloroform hydroxylamine (VII) (Y a is acetyl or benzoyl group) with malononitrile (VIII), in an organic solvent such as THF, in the presence of a base such as triethylamine, 1 hour to 6 hours at 80 ° C. from 0 °C Compound (IX) can be obtained by reaction.
• Compound (II)-(a) is obtained by treating the resulting compound (IX) in an organic solvent such as methanol in the presence of a base such as sodium methoxide or triethylamine at room temperature to 80 ° C. for 30 minutes to 3 hours. Can do.
• an organic solvent such as methanol
• a base such as sodium methoxide or triethylamine
• Compound (VII) can be synthesized according to Synthesis Route 4. That is, compound (XI) can be obtained by treating compound (X) in an organic solvent such as THF or ethanol in the presence of hydrazine monohydrate and palladium carbon at 0 ° C. to room temperature for 30 minutes to 24 hours. . By reacting the obtained compound (XI) with acetyl chloride or benzoyl chloride (XII) in an organic solvent such as THF or DMF in the presence of a base such as triethylamine or potassium carbonate at 0 to 50 ° C. for 1 to 24 hours. Compound (VII) can be obtained.
• Compound (II)-(c) (R 1 is an optionally substituted lower alkyl group) can be produced according to Synthesis Route 5. That is, reacting compound (II)-(a) and alkyl halide (XIII) in an organic solvent such as THF or DMF in the presence of a base such as sodium hydride at 0 to 100 ° C. for 1 to 24 hours. Thus, compound (II)-(c) can be obtained.
• the present compound (I) - (a) and the present compound (I) - a (b) can be synthesized according to synthetic route 6 (Y b is an optionally substituted aryl group or a substituted group A heterocyclic group which may be present. That is, the compound (I)-(c) of the present invention and a halogenating agent such as N-bromosuccinimide and N-chlorosuccinimide in an organic solvent such as DMF at 0 to 100 ° C. for 1 to 24 hours.
• the compound (I)-(a) can be obtained by reacting.
• the resulting compound (I)-(a) of the present invention and boronic acid (XIV) are mixed with tetrakis (triphenylphosphine) palladium (0), tris in a mixed solvent of an organic solvent such as 1,4-dioxane or DMF and water.
• a metal complex catalyst such as (dibenzylideneacetone) dipalladium (0)
• a base such as sodium bicarbonate or triethylamine
• the present compound (I)-(d), the present compound (I)-(e) and the present compound (I)-(f) can be produced according to the synthetic route 7 (Y c represents a substituent).
• the compound (I)-(d) of the present invention can be obtained by reacting for 1 to 24 hours.
• the compound (I)-(a) of the present invention and the boronic acid ester (XVI) are mixed with tetrakis (triphenylphosphine) palladium (0), tris in an organic solvent such as 1,4-dioxane or DMF and water.
• the present compound (I)-(e) is reacted with a metal complex catalyst such as (dibenzylideneacetone) dipalladium (0) in the presence of a base such as sodium hydrogen carbonate or triethylamine at room temperature to 150 ° C. for 1 to 24 hours. ) Can be obtained.
• a metal complex catalyst such as (dibenzylideneacetone) dipalladium (0)
• a base such as sodium hydrogen carbonate or triethylamine
• a base such as sodium hydrogen carbonate or triethylamine
• the present compound (I)-(d) or the present compound (I)-(e) is used in an organic solvent such as methanol or DMF in the presence of palladium carbon in a hydrogen atmosphere at room temperature to 100 ° C. for 1 hour to 24 hours.
• the compound (I)-(f) of the present invention can be obtained by treating with time.
• the compound (I)-(g) and the compound (I)-(h) of the present invention can be produced according to the synthesis route 8. That is, the compound (I)-(i) of the present invention is treated in an organic solvent such as methylene chloride in the presence of a Lewis acid such as boron tribromide at ⁇ 80 ° C. to room temperature for 1 to 24 hours. (I)-(g) can be obtained.
• the resulting compound (I)-(g) of the present invention and halogen compound (XVII) (R 2 has a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent.
• the compound of the present invention can be reacted by reacting in an organic solvent such as THF or DMF in the presence of a base such as potassium carbonate or sodium hydride at 0 to 100 ° C. for 1 to 24 hours.
• I)-(h) can be obtained.
• the compound (I)-(g) of the present invention and the alcohol (XVIII) in an organic solvent such as THF and DMF phosphine such as triphenylphosphine and tributylphosphine, diethyl azodicarboxylate, 1,1 ′-(azodicarbonyl)
• the compound (I)-(h) of the present invention can be obtained by reacting at 0 to 100 ° C. for 1 to 24 hours in the presence of a reagent such as dipiperidine.
• the compound of the present invention produced by the above synthetic route can be made into the above-mentioned salt, hydrate or solvate form using a widely used technique.
• IMAP TM IKK ⁇ assay kit manufactured by Molecular Devices, catalog number R8115
• IMAP TM FP Screening Express kit Molecular Devices
• IKK ⁇ inhibition assay was performed by fluorescence polarization method using the catalog number R8127). As a result, the compound of the present invention showed excellent IKK ⁇ inhibitory activity.
• IKK ⁇ is involved in the expression of various diseases, and the compound of the present invention having an excellent IKK ⁇ inhibitory activity prevents and / or prevents diseases associated with IKK ⁇ inhibitors and / or IKK ⁇ . It is useful as a therapeutic agent.
• inflammatory diseases autoimmune diseases, allergic diseases, infectious diseases, degenerative diseases, vascular diseases, neuro / sensory organ diseases, endocrine / metabolic diseases, neoplastic diseases, congenital diseases, traumatic diseases
• keratitis conjunctivitis, uveitis, osteoarthritis, chronic obstructive pulmonary disease, bronchitis, pneumonia , Hepatitis, pancreatitis, nephritis, sepsis, systemic inflammatory response syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, Sjogren's syndrome, polymyositis, dermatomyositis, asthma, allergy Rhinitis, hives, atopic dermatitis, age-related macular degeneration,
• it is useful as a therapeutic agent for keratitis, conjunctivitis, uveitis, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, diabetic macular edema and / or glaucoma.
• the compound of the present invention can be administered orally or parenterally.
• dosage forms include tablets, capsules, granules, powders, injections, eye drops, suppositories, transdermal absorption preparations, ointments, aerosols (including inhalants), etc., and these are general-purpose technologies. Can be formulated.
• oral preparations such as tablets, capsules, granules, powders are lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate and other excipients, stearic acid, magnesium stearate , Lubricants such as talc, binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, calcium citrate, hydroxypropylmethylcellulose, macrogol, Coating agents such as silicone resins, stabilizers such as ethyl paraoxybenzoate and benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances can be prepared using necessary amounts as necessary. it can.
• Lubricants such as talc
• binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvin
• parenterals such as injections and eye drops are made of isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, sodium phosphate, sodium hydrogen phosphate, sodium acetate.
• isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, sodium phosphate, sodium hydrogen phosphate, sodium acetate.
• Buffering agents such as citric acid, glacial acetic acid, trometamol, surfactants such as polysorbate 80, polyoxy40 stearate, polyoxyethylene hydrogenated castor oil 60, stabilizers such as sodium citrate and sodium edetate, benzal chloride PH adjustment of preservatives such as luconium, paraben, benzotonium chloride, paraoxybenzoate, sodium benzoate, chlorobutanol, hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate Agent, benzyl alcohol, etc. If necessary the soothing agent or the like, using the required amount can be prepared.
• surfactants such as polysorbate 80, polyoxy40 stearate, polyoxyethylene hydrogenated castor oil 60
• stabilizers such as sodium citrate and sodium edetate
• benzal chloride PH adjustment of preservatives such as luconium, paraben, benzotonium chlor
• the dose of the compound of the present invention can be appropriately selected and used depending on symptoms, age, dosage form and the like.
• an oral preparation can be administered usually in an amount of 0.01 to 1000 mg, preferably 1 to 100 mg per day, in one or several divided doses.
• the eye drops are usually administered at a concentration of 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v), once or divided into several times. it can.
• reference compounds 1-2 and 1-3 were obtained using commercially available compounds according to the production method of reference compound 1-1.
• Reference example 2 2-Amino-6-methoxyindole-3-carboxamide (Reference compound 2-1) 2-Amino-4-methoxyindole-3-carboxamide (Reference compound 2-2) To a solution of N-acetyl-N- (3-methoxyphenyl) hydroxylamine (reference compound 1-1, 9.3 g, 50 mmol) and malononitrile (3.4 g, 51 mol) in chloroform (130 mL) was added triethylamine (7.0 mL, 50 mmol) was added and stirred at room temperature for 5 hours. The precipitated solid was collected by filtration, washed with chloroform (50 mL), and dried under reduced pressure at 40 ° C.
• Reference Compounds 2-3 and 2-4 were obtained using Reference Compound 1-2 or 1-3 according to the production method of Reference Compound 2-1.
• Example 1 2-Aminocarbonylamino-6-methoxyindole-3-carboxamide (Compound 1-1) To a solution of 2-amino-6-methoxyindole-3-carboxamide (Reference compounds 2-1, 2.9 g, 14 mmol) in anhydrous tetrahydrofuran (50 mL) at ⁇ 40 ° C. was added trichloroacetyl isocyanate (1.7 mL, 14 mmol). The solution was added dropwise over 10 minutes and stirred for 2.5 hours. Further, 2.0 M ammonia-methanol solution (40 mL, 80 mmol) was added, and the mixture was stirred overnight at room temperature.
• the precipitated solid was collected by filtration and washed with water (50 mL) and chloroform (50 mL).
• the title compound (2.7 g) was obtained as a brown solid (78%) by drying at 50 ° C. under reduced pressure for 2 hours.
• compound 2-2 was used and compound 2-2 was obtained according to the production method of compound 2-1.
• Example 3 2-Aminocarbonylamino-6-propoxyindole-3-carboxamide (Compound 3-1) Under ice-cooling, a suspension of 2-aminocarbonylamino-6-hydroxyindole-3-carboxamide (Compound 2-1, 47 mg, 0.20 mmol) in anhydrous tetrahydrofuran (2 mL) was added to 1-propanol (60 ⁇ L, 0.80 mmol). ), N-tributylphosphine (100 ⁇ L, 0.40 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (98 mg, 0.39 mmol) were added and stirred for 2.5 hours. The mixture was further stirred overnight at room temperature, and then stirred at 50 ° C. for 7 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (7 mg) as a green solid (13%).
• compound 3-2 was obtained according to the production method of compound 3-1.
• Example 6 6- (4-acetylaminophenyloxy) -2- (aminocarbonylamino) indole-3-carboxamide (Compound 6-1) 2-aminocarbonylamino-6- (4-aminophenyloxy) indole-3-carboxamide (Compound 5-1, 40 mg, 0.12 mmol), acetic acid (8 ⁇ L, 0.14 mmol), N, N-diisopropylethylamine (46 ⁇ L) , 0.26 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (48 mg, 0.13 mmol) in anhydrous N, N— Dimethylformamide (1 mL) solution was stirred overnight at room temperature.
• compound 6-2 was obtained according to the production method of compound 6-1.
• Example 7 2-Aminocarbonylamino-5-bromo-6-methoxyindole-3-carboxamide (Compound 7-1) Under ice cooling, N-bromosuccinol was added to a solution of 2-aminocarbonylamino-6-methoxyindole-3-carboxamide (Compound 1-1, 126 mg, 0.51 mmol) in anhydrous N, N-dimethylformamide (1.5 mL). A solution of acid imide (94 mg, 0.53 mmol) in anhydrous N, N-dimethylformamide (1 mL) was added and stirred for 1.5 hours. The mixture was further stirred at room temperature for 2 hours and at 50 ° C. for 3 hours.
• the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL), and then the organic layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the resulting solid was filtered and washed with a mixed solvent (24 mL) of diethyl ether-chloroform (5: 1), and the solid was dried at 40 ° C. under reduced pressure to give the title compound. (50 mg) was obtained as a gray solid (30%).
• Compound 1-4 was obtained using Compound 1-4 according to the production method of Compound 7-1.
• Example 8 2-Aminocarbonylamino-6-methoxy-5-vinylindole-3-carboxamide (Compound 8-1) 2-aminocarbonylamino-5-bromo-6-methoxyindole-3-carboxamide (Compound 7-1, 86 mg, 0.26 mmol), vinylboronic acid pinacol ester (121 ⁇ L, 0.40 mmol), tetrakis (triphenylphosphine) palladium
• (0) 32 mg, 0.027 mmol
• sodium bicarbonate 56 mg, 0.66 mmol
• compounds 8-2 and 8-3 were obtained according to the production method of compound 8-1, using commercially available compounds and compound 7-2.
• Compound of the present invention 1mg Lactose 100mg Corn starch 40mg Carboxymethylcellulose calcium 4.5mg Hydroxypropylcellulose 4mg Magnesium stearate 0.5mg
• a coating agent for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.
• a desired tablet can also be obtained by changing suitably the kind and / or quantity of this invention compound and an additive.
• Capsule (in 150mg) Compound of the present invention 5mg Lactose 135mg Carboxymethylcellulose calcium 4.5mg Hydroxypropylcellulose 4mg Magnesium stearate 1.5mg Desired capsules can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.
• Eye drops (in 100ml) Compound of the present invention 100mg Sodium chloride 900mg Polysorbate 80 500mg Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount Desired eye drops can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.
• IKK ⁇ Inhibitory Activity Measurement Test In order to evaluate the IKK ⁇ inhibitory activity of the compounds of the present invention, an IKK ⁇ inhibition assay by fluorescence polarization was performed. For the assay, use the IMAP TM IKK ⁇ assay kit (Molecular Device, catalog number R8115) or IMAP TM FP Screening Express kit (Molecular device, catalog number R8127) according to the protocol attached to this kit. It was. The specific method is described below.
• Substrate working solution A fluorescently labeled IKK ⁇ substrate peptide (amino acid sequence: GRHDSGLDSMK) was dissolved and diluted with a complete reaction buffer to prepare a 400 nM substrate working solution.
• Enzyme working solution An IKK ⁇ solution (manufactured by Upstate Biotechnology, catalog number 14-485) was diluted with a complete reaction buffer to prepare a 0.2 unit / mL enzyme working solution.
• ATP working solution ATP was dissolved in ultrapure water and then diluted with complete reaction buffer to prepare an 8 ⁇ M ATP working solution.
• IMAP binding solution After diluting and preparing an IMAP binding buffer with ultrapure water, an IMAP binding solution was prepared by diluting an IMAP binding reagent with an IMAP binding buffer.
• test compound solution The test compound was dissolved in dimethyl sulfoxide, and then diluted with a complete reaction buffer to prepare a 4 ⁇ M test compound solution.
• Test method and measurement method 1) A test compound solution, an enzyme working solution, a substrate working solution, and an ATP working solution were added to a 384 well plate in an amount of 5 ⁇ L per well.
• the IKK ⁇ inhibition rate (%) was calculated by the following formula.
• IKK ⁇ inhibition rate (%) 100 ⁇ ⁇ 1 ⁇ (fluorescence polarization value of test compound ⁇ background fluorescence polarization value) / (control fluorescence polarization value ⁇ background fluorescence polarization value) ⁇ (Evaluation results)
• test compounds compounds 1-1, 1-3, 1-4, 2-1, 3-2, 4-1, 4-3, 4-6, 6-1, 8-2
• Table I shows the IKK ⁇ inhibition rate (%) at 1 ⁇ M in 8-3 and 9-1).
• the compounds of the present invention showed excellent IKK ⁇ inhibitory activity. Therefore, the compound of the present invention can be used as an IKK ⁇ inhibitor, and diseases in which IKK ⁇ is involved, such as inflammatory diseases, autoimmune diseases, allergic diseases, infectious diseases, degenerative diseases, vascular diseases, nerve / sensory It is useful as a preventive and / or therapeutic agent for organ diseases, endocrine / metabolic diseases, neoplastic diseases, congenital diseases, traumatic diseases, rejection after organ transplantation, and the like.
• diseases in which IKK ⁇ is involved, such as inflammatory diseases, autoimmune diseases, allergic diseases, infectious diseases, degenerative diseases, vascular diseases, nerve / sensory It is useful as a preventive and / or therapeutic agent for organ diseases, endocrine / metabolic diseases, neoplastic diseases, congenital diseases, traumatic diseases, rejection after organ transplantation, and the like.
• the compound of the present invention has an excellent IKK ⁇ inhibitory activity and is useful as an IKK ⁇ inhibitor.
• the compounds of the present invention are particularly diseases in which IKK ⁇ is involved, such as inflammatory diseases, autoimmune diseases, allergic diseases, infectious diseases, degenerative diseases, vascular diseases, neuro / sensory organ diseases, endocrine / metabolic diseases As a preventive and / or therapeutic agent for tumor diseases, congenital diseases, traumatic diseases, rejection after organ transplantation, etc., more specifically, keratitis, conjunctivitis, uveitis, osteoarthritis, chronic Obstructive pulmonary disease, bronchitis, pneumonia, hepatitis, pancreatitis, nephritis, sepsis, systemic inflammatory response syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, Sjogren's syndrome, multiple Dermatomyositis

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